rs10875714

Positions:

• chr12-47986899-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001844.5(COL2A1):​c.1366-11C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.215 in 1,613,584 control chromosomes in the GnomAD database, including 38,450 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3333 hom., cov: 32)
  • Exomes 𝑓: 0.22 (35117 hom.)
• Consequence: COL2A1 NM_001844.5 intron
• Scores: Splicing: ADA: 0.00001263
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.153

Genes affected

COL2A1 (HGNC:2200): (collagen type II alpha 1 chain) This gene encodes the alpha-1 chain of type II collagen, a fibrillar collagen found in cartilage and the vitreous humor of the eye. Mutations in this gene are associated with achondrogenesis, chondrodysplasia, early onset familial osteoarthritis, SED congenita, Langer-Saldino achondrogenesis, Kniest dysplasia, Stickler syndrome type I, and spondyloepimetaphyseal dysplasia Strudwick type. In addition, defects in processing chondrocalcin, a calcium binding protein that is the C-propeptide of this collagen molecule, are also associated with chondrodysplasia. There are two transcripts identified for this gene. [provided by RefSeq, Jul 2008]

COL2A1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 12-47986899-G-A is Benign according to our data. Variant chr12-47986899-G-A is described in ClinVar as [Benign]. Clinvar id is 258210.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-47986899-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.299 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL2A1	NM_001844.5	c.1366-11C>T		intron_variant		ENST00000380518.8	NP_001835.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL2A1	ENST00000380518.8	c.1366-11C>T		intron_variant		1	NM_001844.5	ENSP00000369889.3
COL2A1	ENST00000337299.7	c.1159-11C>T		intron_variant		1		ENSP00000338213.6
COL2A1	ENST00000493991.5	n.290-11C>T		intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.203 AC: 30918 AN: 152058 Hom.: 3329 Cov.: 32

Gnomad AFR AF: 0.173

Gnomad AMI AF: 0.0800

Gnomad AMR AF: 0.204

Gnomad ASJ AF: 0.259

Gnomad EAS AF: 0.312

Gnomad SAS AF: 0.167

Gnomad FIN AF: 0.156

Gnomad MID AF: 0.250

Gnomad NFE AF: 0.221

Gnomad OTH AF: 0.226

GnomAD3 exomes AF: 0.198 AC: 49697 AN: 251484 Hom.: 5326 AF XY: 0.199 AC XY: 27112 AN XY: 135912

Gnomad AFR exome AF: 0.170

Gnomad AMR exome AF: 0.132

Gnomad ASJ exome AF: 0.246

Gnomad EAS exome AF: 0.305

Gnomad SAS exome AF: 0.162

Gnomad FIN exome AF: 0.161

Gnomad NFE exome AF: 0.215

Gnomad OTH exome AF: 0.221

GnomAD4 exome AF: 0.216 AC: 315215 AN: 1461408 Hom.: 35117 Cov.: 35 AF XY: 0.214 AC XY: 155888 AN XY: 727000

Gnomad4 AFR exome AF: 0.177

Gnomad4 AMR exome AF: 0.139

Gnomad4 ASJ exome AF: 0.252

Gnomad4 EAS exome AF: 0.286

Gnomad4 SAS exome AF: 0.163

Gnomad4 FIN exome AF: 0.161

Gnomad4 NFE exome AF: 0.222

Gnomad4 OTH exome AF: 0.231

GnomAD4 genome AF: 0.203 AC: 30935 AN: 152176 Hom.: 3333 Cov.: 32 AF XY: 0.200 AC XY: 14873 AN XY: 74416

Gnomad4 AFR AF: 0.174

Gnomad4 AMR AF: 0.204

Gnomad4 ASJ AF: 0.259

Gnomad4 EAS AF: 0.311

Gnomad4 SAS AF: 0.166

Gnomad4 FIN AF: 0.156

Gnomad4 NFE AF: 0.221

Gnomad4 OTH AF: 0.223

Alfa AF: 0.206 Hom.: 1027

Bravo AF: 0.206

Asia WGS AF: 0.209 AC: 726 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 21, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Stickler syndrome type 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Type II Collagenopathies Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	7.4
DANN	Benign	0.42

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000013
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs10875714; hg19: chr12-48380682; COSMIC: COSV61528084; COSMIC: COSV61528084;